Specific inflammatory osteoclast precursors induced during chronic inflammation give rise to highly active osteoclasts associated with inflammatory bone loss

Elevated osteoclast (OC) activity is a major contributor to inflammatory bone loss (IBL) during chronic inflammatory diseases. However, the specific OC precursors (OCPs) responding to inflammatory cues and the underlying mechanisms leading to IBL are poorly understood. We identified two distinct OCP subsets: Ly6C(hi)CD11b(hi) inflammatory OCPs (iOCPs) induced during chronic inflammation, and homeostatic Ly6C(hi)CD11b(lo) OCPs (hOCPs) which remained unchanged. Functional and proteomic characterization revealed that while iOCPs were rare and displayed low osteoclastogenic potential under normal conditions, they expanded during chronic inflammation and generated OCs with enhanced activity. In contrast, hOCPs were abundant and manifested high osteoclastogenic potential under normal conditions but generated OCs with low activity and were unresponsive to the inflammatory environment. Osteoclasts derived from iOCPs expressed higher levels of resorptive and metabolic proteins than those generated from hOCPs, highlighting that different osteoclast populations are formed by distinct precursors. We further identified the TNF-alpha and S100A8/A9 proteins as key regulators that control the iOCP response during chronic inflammation. Furthermore, we demonstrated that the response of iOCPs but not that of hOCPs was abrogated in tnf-alpha(-/-) mice, in correlation with attenuated IBL. Our findings suggest a central role for iOCPs in IBL induction. iOCPs can serve as potential biomarkers for IBL detection and possibly as new therapeutic targets to combat IBL in a wide range of inflammatory conditions.

Automated summary

This study identified two distinct subsets of osteoclast precursors (OCPs) and revealed their different response to inflammatory cues and their role in inflammatory bone loss (IBL). The findings indicate that the Ly6C(hi)CD11b(hi) inflammatory OCPs (iOCPs) play a central role in IBL induction while the Ly6C(hi)CD11b(lo) homeostatic OCPs (hOCPs) remain stable and less affected by inflammation. This study provides insights into the understanding of IBL and suggests iOCPs as potential biomarkers and therapeutic targets for IBL.